Solution and Solid Phase Synthesis of Unusual a-Amino Acids From

doublets. Variable temperature 'H-NMR studies in DMF-d7 failed to disprove the notion
that the minor doublet was due to the presence of rotamers.
In an effort to rationalize the modest selectivity we were encountering, we
attempted to identify the stereochemistry of methylation. Lactones have been used
extensively to determine relative stenxichemistry and so 4-73 was reduced with
DIBALH and the OB0 ester ring-opened with 20% acetic acid to the mhpd ester 4.83.
then lactonized under acidic conditions @-TsOH in refluxing benzene) to give lactone
484 (Scheme 4.20). The relative stereochemistry was initially assigned as 2&4R after
decoupling 'H-NMR experiments showed the proton at C4 to be axial with a coupling
constant of 10.3Hz (J4an5ax). Typical values for the ABX axial, axial proton coupling in
lactones are S-IOHZ.~ However, the assipment of this stereochemistry was determined
to be incorrect since a crystal structure of 4.73 was eventually obtained (Figure 4.3) and
X-ray anaiysis indicated S,4S stereochemistry (Appendix A). Presumably, under the
themodynarnic conditions used to lactonize 4.83, epimerization occurs at the a-carbon of
2S,4S-4.83 to convert the dihydroxy ester to 2R,4S4m83 which then lactonizes to 2R,4S-
4.84. An alternative mechanism involves the lactone 2S,4S4m84 racernizing to the more
stable 2R.4S-lactone 4.84 in which both CH3 and CbzHN equatoriai?
In an effort to irrefutably determine the diastereomenc ratio of methylation, we
unsuccessfully attempted to epimerize the varbon of y-methylglutamate 4.73 with
excess LiHMDS; however, excess LDA at -78OC followed by aqueous work-up
successfully epimerized the y-carbon to give a 1: 1 mixture of the 2S94S:2S,4R y-
methylglutamate derivative. Although the pmethyl protons had essentially identical
chernical shifts for both 2S74S-4.73 and 2S,4R-4.74 diastenomers, the P- (1.65-1 -85 ppm